U.S. patent application number 10/968464 was filed with the patent office on 2005-11-03 for controlled viscosity tissue adhesive.
Invention is credited to Hammerslag, Julius G., Quinn, James V..
Application Number | 20050245966 10/968464 |
Document ID | / |
Family ID | 35188093 |
Filed Date | 2005-11-03 |
United States Patent
Application |
20050245966 |
Kind Code |
A1 |
Hammerslag, Julius G. ; et
al. |
November 3, 2005 |
Controlled viscosity tissue adhesive
Abstract
Disclosed are methods and compositions for closing and sealing a
wound, laceration, incision, or other percutaneous opening using an
adhesive. In one preferred embodiment, the sides of the
percutaneous opening are brought together in apposition and the
adhesive is applied topically over the apposed opening and the skin
adjacent thereto. Adhesives used in the methods of the preferred
embodiments exhibit sufficient viscosity to substantially prevent
flow of the adhesive into the percutaneous opening. Adhesives may
also be used in surgical applications, as a covering for a trauma
to the outer surface of the skin, or as a secondary means of
closure in combination with other means of closure, including
staples and sutures. In a preferred embodiment, the adhesive is a
adhesive comprising cyanoacrylate monomer, cyanoacrylate polymer,
and a plasticizer.
Inventors: |
Hammerslag, Julius G.; (La
Quinta, CA) ; Quinn, James V.; (Portola, CA) |
Correspondence
Address: |
LEACH PATENT SERVICES
5 EAST ALDINE DRIVE
HOCKESSIN
DE
19707
US
|
Family ID: |
35188093 |
Appl. No.: |
10/968464 |
Filed: |
October 19, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10968464 |
Oct 19, 2004 |
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10145581 |
May 13, 2002 |
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10145581 |
May 13, 2002 |
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09702013 |
Oct 30, 2000 |
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6386203 |
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09702013 |
Oct 30, 2000 |
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09339146 |
Jun 24, 1999 |
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6155265 |
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09339146 |
Jun 24, 1999 |
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09078944 |
May 14, 1998 |
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09078944 |
May 14, 1998 |
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08991823 |
Dec 17, 1997 |
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Current U.S.
Class: |
606/214 |
Current CPC
Class: |
A61L 24/06 20130101;
A61L 24/001 20130101; C08L 35/04 20130101; A61L 24/06 20130101 |
Class at
Publication: |
606/214 |
International
Class: |
A61L 015/16 |
Claims
What is claimed is:
1. A tissue adhesive, comprising: about 70-95% by volume of a
mixture of first and second cyanoacrylate monomers, each having the
general formula (I): 3wherein R is alkyl; and the first
cyanoacrylate monomer has at least 3 carbon atoms and the second
cyanoacrylate monomer has no more than 10 carbon atoms; about 1-15%
by volume cyanoacrylate polymer; and about 2-15% by volume
plasticizer.
2. A tissue adhesive according to claim 1, wherein the viscosity is
within the range of from about 100 to about 50,000 centipoise.
3. A tissue adhesive according to claim 1, wherein the viscosity is
within the range of from about 100 to about 5,000 centipoise.
4. A tissue adhesive according to claim 1, wherein the adhesive
comprises about 80-90% cyanoacrylate monomer, about 5-10%
cyanoacrylate polymer, and about 5-10% plasticizer.
5. A tissue adhesive according to claim 1, wherein the first
cyanoacrylate monomer is octylcyanoacrylate and the second
cyanoacrylate monomer is butylcyanoacrylate.
6. A tissue adhesive according to claim 1, wherein the monomer
mixture comprises about 50% to about 95% of the first cyanoacrylate
monomer and about 5% to about 50% of the second cyanoacrylate
monomer.
7. A tissue adhesive according to claim 7, wherein the monomer
mixture comprises about 65% to about 75% of the first cyanoacrylate
monomer and about 25% to about 35% of the second cyanoacrylate
monomer.
8. A tissue adhesive according to claim 7, wherein the first
cyanoacrylate monomer is octylcyanoacrylate and the second
cyanoacrylate monomer is butylcyanoacrylate.
9. A tissue adhesive according to claim 1, wherein the
cyanoacrylate polymer comprises poly(octylcyanoacrylate).
10. A tissue adhesive according to claim 1, wherein the plasticizer
is tributyl citrate.
11. A method of closing a percutaneous opening, having a first
dermal surface on a first side of the opening and a second dermal
surface on a second side of the opening and generally coplanar with
the first dermal surface, the method comprising the step of:
applying an adhesive layer across at least a portion of the first
and second dermal surfaces and spanning the opening, wherein the
adhesive comprises one or more cyanoacrylate monomers,
cyanoacrylate polymer, and plasticizer; and wherein the adhesive
exhibits a sufficient viscosity to substantially prevent flow of
the adhesive into the opening.
12. A method as in claim 11, wherein the viscosity is within the
range of from about 100 to about 50,000 centipoise.
13. A method as in claim 11, wherein the viscosity is within the
range of from about 100 to about 5,000 centipoise.
14. A method as in claim 11, wherein the viscosity is at least
about 100 centipoise.
15. A method as in claim 11, wherein the adhesive comprises about
70-95% cyanoacrylate monomer, about 1-15% cyanoacrylate polymer,
and about 2-15% plasticizer.
16. A method as in claim 15, wherein the adhesive comprises about
80-90% cyanoacrylate monomer, about 5-10% cyanoacrylate polymer,
and about 5-10% plasticizer.
17. A method as in claim 11, wherein the cyanoacrylate monomer
comprises a mixture of octylcyanoacrylate and
butylcyanoacrylate.
18. A method as in claim 17, wherein the cyanoacrylate monomer
comprises about 60% to about 80% octylcyanoacrylate and about 20%
to about 40% butylcyanoacrylate.
19. A method as in claim 17, wherein the cyanoacrylate monomer
comprises about 65% to about 75% octylcyanoacrylate and about 25%
to about 35% butylcyanoacrylate.
20. A method as in claim 11, wherein the cyanoacrylate polymer
comprises poly(octylcyanoacrylate).
21. A method as in claim 11, wherein the plasticizer is tributyl
citrate.
22. A method as in claim 11, wherein the adhesive layer has a
thickness over the opening of at least 1 millimeter.
23. A method of closing and sealing a joint formed between a tissue
of a patient and a second surface, comprising: positioning a tissue
of a patient adjacent to a second surface; securing the tissue to
the second surface using a primary closure modality to form a
joint; delivering an adhesive comprising cyanoacrylate monomer,
cyanoacrylate polymer, and a plasticizer to the joint; and
permitting the adhesive to polymerize.
24. A method as in claim 23, wherein the second surface is an
autologous tissue, allograph tissue, animal tissue, biologically
compatible metal, polymeric material, or prosthetic device.
25. A method as in claim 23, wherein the primary closure modality
is sutures or staples.
26. A method as in claim 23, wherein the tissue and the second
surface are adjacent surfaces of the skin of a patient.
27. A method of closing and sealing a wound in a patient,
comprising the steps of: identifying a percutaneous wound having
first and second sides; delivering a layer of wound closure
adhesive comprising one or more cyanoacrylate monomers,
cyanoacrylate polymer, and plasticizer to the surface of skin on
each of the first and second sides and across the wound in a
quantity sufficient to retain closure and sealing of said wound;
and restraining adhesive from entering the wound.
28. A method as in claim 27, wherein the restraining step comprises
providing the wound closure adhesive with a sufficient viscosity to
extend in a layer across the wound, while substantially preventing
the adhesive from entering the wound.
29. A method as in claim 28, wherein the viscosity is at least 100
centipoise.
30. A method of covering a trauma to an outer layer of a skin in a
patient comprising: delivering an adhesive comprising cyanoacrylate
monomer, cyanoacrylate polymer, and a plasticizer to a surface of
the skin covering an area of the trauma to the outer layer of the
skin in a quantity sufficient to cover said trauma; and permitting
the adhesive to polymerize.
31. A method as in claim 30, further comprising applying an aqueous
solution to the trauma prior to delivering the adhesive.
32. A method as in claim 30, wherein the adhesive has a
prepolymerization viscosity of at least about 100 centipoise.
33. A method as in claim 30, wherein the trauma is selected from
the group consisting of abrasions, scrapes, burns, blisters,
bedsores, ulcers, chapping, and chafing.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation-in-part of application Ser. No.
10/145,581, filed May 13, 2002, which is a continuation of
application Ser. No. 09/702,013, filed Oct. 13, 2000, which is a
continuation of application Ser. No. 09/339,146, filed Jun. 24,
1999, now U.S. Pat. No. 6,155,265, issued Dec. 5, 2000, which is a
continuation-in-part of application Ser. No. 09/078,944, filed May
14, 1998, now abandoned, which is a continuation-in-part of
application Ser. No. 08/991,823 filed Dec. 17, 1997, now abandoned,
and also claims priority to U.S. Provisional Application Ser. No.
60/602,975, filed: Aug. 19, 2004, the disclosures of which are
incorporated by reference herein in their entireties.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to medical and surgical tissue
adhesives. In one embodiment, the adhesive is of the type useful
for bonding adjacent sections of skin separated by percutaneous
incision or traumatic injury.
[0004] 2. Description of the Related Art
[0005] Every year, over 10 million traumatic wounds are treated by
emergency physicians in the United States. A great many incisions
ranging from a few millimeters to several centimeters in length are
closed each year by medical personnel. Countless more less serious
wounds are treated by non-medical persons, such as athletic
trainers, parents of an injured child, or the injured individual
himself.
[0006] Small wounds and lacerations can be treated by simply
bandaging the wound or by using tape to keep the edges of the wound
in apposition. Such methods can be performed with a minimum of time
and training, as well as causing little or no additional trauma to
the wound or causing the patient additional pain.
[0007] More serious wounds or incisions are generally treated by
conventional methods, such as suturing. Suturing requires the use
of a needle and often involves a local anesthetic. Suturing can be
costly because it is time-intensive and the procedure requires that
the individual performing it have some medical training.
Additionally, suturing can be painful and the use of needles may
cause further distress for an already traumatized patient, as well
as expose medical personnel to potential needlestick injury.
Furthermore, because most sutures used topically do not dissolve,
the patient generally must make a return visit at a later date for
the often uncomfortable procedure of removal of the sutures.
[0008] In recent years, cyanoacrylate tissue adhesives have been
tried as an alternative for such conventional methods. The most
commonly used cyanoacrylates for wound closure include octyl- and
butylcyanoacrylate, have some advantages over suturing, such as
faster and less painful closure. These monomers like all
cyanoacrylate monomers have several drawbacks. One drawback is that
they have a very low viscosity. The low viscosity makes precise
application difficult, in that the adhesive flows over areas of the
skin surface well beyond the immediate region of the closure and
that the adhesive is readily drawn into the wound, effectively
creating a barrier between the two tissue surfaces which are
desirably rejoined in the natural healing process thereby blocking
epithelealization and fibroblast growth. Furthermore, certain
cyanoacrylate monomers and formulations form a closure which is
hard, brittle, and inflexible, and which sets up too quickly to
allow for adjustment of the opposing skin surfaces following its
application.
SUMMARY OF THE INVENTION
[0009] There remains a need for a simple and effective method and
composition for effecting wound closure. Preferably, the method and
composition can be utilized with minimal training time and risk of
error, and will not materially increase complications,
immunogenicity, scarring, infection, or other negative factors.
[0010] In accordance with one aspect, there is provided a tissue
adhesive. The tissue adhesive comprises about 1-15% by volume
cyanoacrylate polymer; about 2-15% by volume plasticizer and about
70-95% by volume of a mixture of first and second cyanoacrylate
monomers, each having the general formula (I): 1
[0011] wherein R is alkyl and the first cyanoacrylate monomer has
at least about 3 carbon atoms and the second cyanoacrylate monomer
has no more than about 10 carbon atoms.
[0012] In accordance with another of the preferred embodiments,
there is provided a method of closing a percutaneous opening,
having a first dermal surface on a first side of the opening and a
second dermal surface on a second side of the opening and generally
coplanar with the first dermal surface. The method comprises
applying an adhesive layer across at least a portion of the first
and second dermal surfaces and spanning the opening, wherein the
adhesive comprises a blended cyanoacrylate monomer, cyanoacrylate
polymer and plasticizer; and exhibits a sufficient viscosity to
substantially prevent flow of the adhesive into the opening.
[0013] In accordance with another preferred embodiment, there is
provided a method of closing and sealing a joint formed between a
tissue of a patient and a second surface, comprising positioning a
tissue of a patient adjacent to a second surface; securing the
tissue to the second surface using a primary closure modality to
form a joint; delivering an adhesive comprising cyanoacrylate
monomer, cyanoacrylate polymer, and a plasticizer to the joint; and
permitting the adhesive to polymerize.
[0014] In accordance with a further embodiment, there is provided a
method of closing and sealing a wound in a patient. The method
comprises the steps of identifying a percutaneous wound having
first and second sides, delivering a layer of wound closure
adhesive comprising cyanoacrylate monomer, cyanoacrylate polymer,
and a plasticizer to the surface of skin, blood vessel or other
tissue on each of the first and second sides and across the wound
in a quantity sufficient to retain closure and sealing of said
would, and restraining the adhesive from entering the wound.
[0015] In accordance with a further embodiment, there is provided a
method of covering a trauma to an outer layer of a skin in a
patient. The method comprises delivering an adhesive comprising
cyanoacrylate monomer, cyanoacrylate polymer, and a plasticizer to
a surface of the skin spanning an area of the trauma to the outer
layer of the skin in a quantity sufficient to cover said trauma;
and permitting the adhesive to polymerize.
[0016] Further features and advantages of the present invention
will become apparent to those of skill in the art in view of the
detailed description of preferred embodiments which follows, when
considered together with the attached drawings and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 is a cross-section of a rollerball
container-applicator as can be used to apply adhesives in
accordance with the preferred embodiments.
[0018] FIG. 2 depicts the use of a rollerball container-applicator
of the type in FIG. 1 to deliver adhesive to a topical wound to
effect closure in accordance with the preferred embodiments.
[0019] FIG. 3 is a view of an alternate container-applicator for
use in accordance with the preferred embodiments.
[0020] FIG. 4 is a cross-section of the container-applicator of
FIG. 3.
[0021] FIG. 5 is a blown-up view of the applicator tip of the
container-applicator of FIG. 3 showing the placement of a
break-away sealing tip.
[0022] FIG. 6 is a cross-section of a percutaneous opening or wound
which has been closed and sealed according to the preferred
embodiments.
[0023] FIG. 7 is a view of a tube container-applicator for use in
accordance with the preferred embodiments.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0024] Several considerations come into play when a closing
percutaneous opening, such as a wound or incision. The
considerations include providing a closure having adequate strength
to resist opening or rupture and providing a closure which protects
the opening, but does not at the same time substantially interfere
with the normal healing processes. One method that can be used is
the application of an adhesive. An adhesive can be used either with
or without additional closure means.
[0025] When the adhesive used is a liquid, it presents a different
set of considerations as compared to solid materials and other
conventional methods of closure, such as staples, sutures, and
bandages. Several of these considerations have to do with the
viscosity of the adhesive.
[0026] In discussing the viscosity of the adhesives in the context
of preferred embodiments, the viscosity referred to herein is the
viscosity of the adhesive at the time it is being applied.
Following application, the adhesive will increase in viscosity
until the adhesive "sets up" to form the final solid or relatively
solid state of the adhesive closure due to physical or chemical
mechanisms in the adhesive or adhesive preparation, including, but
not limited to, curing, cross-linking, polymerizing, and
evaporation of solvent. Once the adhesive has set up to form the
closure, it will preferably take a solid form, which can be
flexible, rubbery or stiff, with firm but flexible closures being
preferred. Furthermore, unless specifically referenced otherwise,
all percentages herein are percentages by volume.
[0027] Adhesives used in accordance with preferred embodiments
preferably have a viscosity low enough such that they flow (and can
be spread) when acted upon by gravity or some other force, such as
being squeezed out of a tube or spread with an applicator. This
action allows for the adhesive to wet the skin adjacent the opening
and also allows for application of the adhesive by a variety of
methods. On the other hand, the viscosity of the adhesive during
application is preferably not so low that the adhesive becomes
runny and flows far beyond the general vicinity of the intended
application surface or that it flows into the opening itself. This
is an especially important consideration, because if the adhesive
flows a substantial distance into the opening, it can block the
surfaces that are to be healed together, and thus can actually
impede or prevent the healing process by acting as a barrier to the
migration of basal cells and collagen in the natural healing of a
wound. Seepage into the wound is a significant problem with
adhesives known in the art, such as liquid cyanoacrylates which
have a very low viscosity and will, when placed on a wound, run
into the wound or be drawn therein via capillary action.
Accordingly, a preferred adhesive polymerizes and sets before it
runs into a wound, incision, opening, or into undesired areas. An
example of a preferred situation of applying an adhesive is
applying a layer of the adhesive to a horizontal wound plane and
then moving the wound plane to a vertical position and allowing the
adhesive to polymerize without running.
[0028] To achieve at least some of the properties discussed above,
the adhesive used to close a percutaneous opening in accordance
with the preferred embodiments preferably has sufficient viscosity,
realizing that "sufficient viscosity" is a combination of the
volume and mass of material used as well as the setting times of
the adhesive used to achieve the purpose. In general this is a
viscosity greater than about 100 centipoise, but may be as low as
50 cps if initiators or accelerators are use to speed the rate of
curing so that the adhesive sets before flowing into unwanted
areas. Although very high viscosity materials can be used in
accordance with the preferred embodiments, viscosities of less than
about 100,000 are generally used, and it is preferred that the
viscosity be less than about 5,000 centipoise, or less than about
2500 cp such that the adhesive maintains a reasonable amount of
workability and ability to flow under pressure. In a preferred
embodiment, the viscosity of the adhesive is within the range of
from about 100 to about 10,000 centipoise, including about 200 cp,
300 cp, 400 cp, 500 cp, 600 cp, 700 cp, 800 cp, 900 cp, 1000 cp,
2000 cp, 3000 cp, 4000 cp, 5000 cp, and 7500 cp. Ranges of
viscosities which comprise the preceding viscosities and those
between the recited viscosities and are limited at their high and
low ends by any two of the recited viscosities are also
contemplated (e.g. 300-700 cp, 400-900 cp, etc.).
[0029] Adhesives according to preferred embodiments preferably
comprise cyanoacrylates. Cyanoacrylates have the general formula as
shown below. As also shown below, cyanoacrylates can polymerize to
polycyanoacrylates in the presence of water from the air or trace
amounts of moisture on the surface to which the adhesive is being
applied. Upon application to the surface, the monomer undergoes an
exothermic hydroxylation reaction that results in polymerization.
2
[0030] In the formula above, R may be any organic group which does
not interfere with the polymerization of the monomer to form the
polycyanoacrylate. In a preferred embodiment, R is alkyl which
includes straight-chain, branched, and cyclic groups, and include
from about 2 to about 12 carbon atoms, more preferably from about 3
to about 10 carbon atoms.
[0031] A cyanoacrylate can been modified to increase its viscosity
and/or decrease its polymerization rate. The viscosity of the
cyanoacrylate can be increased to a gel or paste form by chemical
modification of the cyanoacrylate molecule and/or by the presence
of one or more viscosifying agents.
[0032] Examples of compounds used in connection with certain
embodiments include polymerizable cyanoacrylates that have been
cross-linked or co-polymerized with other compounds that can alter
elasticity, modify viscosity, aid biodegradation or change some
other property of the resulting material. For example, polyacrylic
acid having a molecular weight of 200,000 to 600,000 can be
cross-linked to a cyanoacrylate to form compounds that allow the
absorbability to be coordinated with the tissue regeneration rate
and can feature higher elasticity than cyanoacrylates alone.
Absorbability is generally unnecessary for topical applications,
with the adhesive film simply falling off in a few days.
[0033] In a preferred embodiment, the adhesive comprises the
following components: 1) cyanoacrylate monomer, 2) cyanoacrylate
polymer, and 3) plasticizer. The cyanoacrylate monomer gives
adhesive properties. In the choice of a cyanoacrylate monomer for
adhesiveness, factors to be considered include rate of
polymerization, tensile strength, and brittleness and flexibility.
These factors are also balanced with the choice of the other
ingredients, the cyanoacrylate polymer and plasticizer. The
cyanoacrylate polymer which, having a high molecular weight, is
used as a viscosifying agent and adds flexibility. The
cyanoacrylate polymer also gives tensile strength. The plasticizer
enhances flexibility and resilience. Additionally, to the
formulations of the preferred embodiments, any of a variety of
other additives can also be added, such as bacteriostatic agents,
anti-inflammatory agents, and preservatives, stabilizers and the
like, as will be understood by those of skill in the art. In some
embodiments, formulations of tissue adhesives can additionally
comprise one or more optional additives, such as polymers,
viscosity modifiers, colorants, perfumes, anti-diffusion agents,
salts, antibiotics, anti-microbials, stabilizers, desiccants,
catalysts, or agents that alter polymerization rate.
[0034] Among the reasons that cyanoacrylates are preferred for use
in tissue adhesives are their several particular advantages as an
adhesive compound. First, they can harden almost instantaneously on
contact with surfaces having moisture thereon. These contact areas
include most tissues and surfaces in and on the body of an animal,
such as a human. Second, experiments by the inventor indicate that
cyanoacrylate sealed vascular punctures can withstand several times
the maximum potential systolic pressure, and hence, would not be
expected to fail when used to seal most surface wounds.
Cyanoacrylates are also naturally thrombogenic. This property is an
advantage in certain applications as it promotes the first step in
healing.
[0035] Preferred compounds to be used in the adhesives disclosed
herein include at least one of the biologically suitable monomer
compounds within the cyanoacrylate family. The cyanoacrylate family
includes methyl cyanoacrylate, ethyl cyanoacrylate, n-propyl
cyanoacrylate, isopropyl cyanoacrylate, n-butyl cyanoacrylate,
isobutyl cyanoacrylate, n-amyl cyanoacrylate, isoamyl
cyanoacrylate, hexylcyanoacrylate, octylcyanoacrylate,
3-acetoxypropyl cyanoacrylate, 2-methoxypropyl cyanoacrylate,
3-chloropropyl cyanoacrylate, benzyl cyanoacrylate, phenyl
cyanoacrylate, alkenyl cyanoacrylate, butyl-2-cyanoacrylate,
alkoxyalkyl 2-cyanoacrylates, fluorinated 2-cyanoacrylates, and
carbalkoxyalkyl cyanoacrylates, depending upon acceptable toxicity
and other properties for a given application. In a preferred
embodiment, the adhesive compound comprises octylcyanoacrylate and
butylcyanoacrylate. Other members of the cyanoacrylate family may
be commercially available or can be synthesized according to
published procedures or analogous methods as is within the
abilities of one skilled in the art.
[0036] Among the preferred cyanoacrylate monomers are
octylcyanoacrylate, in which R is octyl, and butylcyanoacrylate, in
which R is butyl. The properties of the cyanoacrylate can be
modified by altering the R group of the alkoxycarbonyl group. The
shorter-chain derivatives tend to have a higher degree of tissue
toxicity than the longer-chain derivatives. However, the
shorter-chain derivatives provide advantages as a dermal adhesive
according to its properties. Shorter-chain derivatives provide
stronger bonds and more rapid curing. For example,
polybutylcyanoacrylates are rigid when dry, but provide a strong
bond and polyoctylcyanoacrylates are more flexible when dry, but
produce a weaker bond. However, the shorter-chain derivatives
provide advantages as a dermal adhesive according to its
properties. Shorter-chain derivatives provide stronger bonds and
more rapid curing. For example, polybutylcyanoacrylates are rigid
when dry, but provide a strong bond and polyoctylcyanoacrylates are
more flexible when dry, but produce a weaker bond.
[0037] Inflammation, tissue necrosis, granulation formation, and
wound breakdown can occur when cyanoacrylates are implanted
subcutaneously. The process causing the histological toxicity is
thought to be related to a general foreign body reaction and the
by-products of degradation, cyanoacetate and formaldehyde. The
local concentrations of these breakdown products are proportional
to the rate of degradation (an aqueous degradation process) of the
parent compound. Therefore, slower degradation rate results in less
toxicity to the tissues. This phenomenon is explained by the
hypothetical possibility that slowly degrading compounds release
degradation products more gradually, thereby permitting more
effective clearance and invoke a less intense inflammatory
response. The longer-chain compounds degrade much more slowly than
the shorter-chain compounds, hence the lower reactivity and
toxicity of the longer-chain compounds.
[0038] There is a wide variation in the rates and facility of in
vivo biodegradation of polymers made from cyanoacrylate monomers
which can be used as adhesive compounds in the preferred
embodiments and this wide variation is contemplated. Generally,
polymers of cyanoacrylates which have substituents that are small
and/or contain one or more oxygen-containing functional groups
(e.g. ether, ester, carbonyl) appear to have increased
biodegradability rates. Cyanoacrylates having long chain alkyl
groups lacking in oxygen-containing functional groups as
substituents can tend to form polymers which biodegrade more
slowly. There are also indications in the literature that the
biodegradation rate of cyanoacrylate polymers is affected by the
polymer molecular weight and crystallinity of the polymer.
[0039] There are several studies of biodegradation rates of
polymers formed by various members of the cyanoacrylate family in
the scientific and medical literature. It is within the abilities
of one of skill in the art to use such information in the
literature along with routine experimentation in order to choose a
member of the cyanoacrylate family with suitable biodegradation
characteristics for use in accordance with the preferred
embodiments.
[0040] The above-listed members of the cyanoacrylate family, as
well as other members of the cyanoacrylate family and other
adhesive compounds that fall within the scope of the preferred
embodiments and are not listed above, can differ in their
properties when used in a adhesive. The efficacy, histotoxicity,
and other medically relevant properties of above-listed and other
members of the cyanoacrylate family can be readily determined by
routine experimentation by one of ordinary skill in the art or by
review of the medical literature. Such experimentation will enable
one skilled in the art to choose optimal cyanoacrylate or other
adhesive compounds for use in the adhesive of the preferred
embodiments for a desired specific application.
[0041] In preferred embodiments, cyanoacrylate polymer is used as a
viscosifying agent. A long chain cyanoacrylate polymer can also aid
in overcoming brittleness of the adhesive material. Also among the
properties that change with the quantity of cyanoacrylate polymer
used are viscosity and polymerization rate. Increasing the
percentage of cyanoacrylate polymer in the adhesive will increase
the viscosity of the adhesive. Increased viscosity provides for
easier application of the adhesive on tissues, as viscous adhesives
stay where they are placed and thus decrease the incidence of
running or dripping onto other surfaces or tissues, or leaking in
between sides of an opening to be closed. Decreased polymerization
rates allow more time for a practitioner to place and adjust the
surfaces that are to be sealed. Where the polymerization time is
short, there can be little if any margin for error before the
surfaces are sealed. The longer polymerization time has an
additional benefit. Since the polymerization process is exothermic,
decreasing the polymerization rate decreases the rate that heat is
released by the adhesive, resulting in a lower temperature in the
adhesive and surrounding tissues during polymerization.
[0042] Preferred cyanoacrylate polymer compounds to be used in the
viscosifying agent of the preferred embodiments include a
biologically suitable polymer compounds made from at least one
member within the cyanoacrylate family. As stated above, the
cyanoacrylate family includes methyl cyanoacrylate, ethyl
cyanoacrylate, n-propyl cyanoacrylate, isopropyl cyanoacrylate,
n-butyl cyanoacrylate, isobutyl cyanoacrylate, n-amyl
cyanoacrylate, isoamyl cyanoacrylate, hexylcyanoacrylate
octylcyanoacrylate, decylcyanoacrylate, 3-acetoxypropyl
cyanoacrylate, 2-methoxypropyl cyanoacrylate, 3-chloropropyl
cyanoacrylate, benzyl cyanoacrylate, phenyl cyanoacrylate, alkenyl
cyanoacrylate, butyl-2-cyanoacrylate, alkoxyalkyl 2-cyanoacrylates,
fluorinated 2-cyanoacrylates, and carbalkoxyalkyl cyanoacrylates,
depending upon acceptable toxicity and other properties for a given
application. Other members of the cyanoacrylate family may be
suitable to form the cyanoacrylate polymer for use as a
viscosifying agent. Generally speaking, cyanoacrylate polymers
having longer chain R groups are preferred. Examples of
cyanoacrylate polymers having a longer chain R group are
poly(octylcyanoacrylate) and poly(decylcyanoacrylate).
[0043] Another component in preferred embodiments of tissue
adhesives is a plasticizer. Preferably, the plasticizer is suitable
for use in the mammalian body. Examples of suitable plasticizers
include, but are not limited to, tributyl citrate, acetyl tributyl
citrate, dimethyl sebacate, diethylsebacate, triethyl phosphate,
tri(2-ethyl-hexyl)phosphate, tri(p-cresyl) phosphate, glyceryl
triacetate, glyceryl tributyrate, dioctyl adipate, isopropyl
myrisate, butyl sterate, lauric acid, trioctyl trimelliate, dioctyl
glutatrate and mixtures thereof. Tributyl citrate is preferred.
[0044] In a preferred embodiment, the adhesive comprises about
70-95% cyanoacrylate monomer by volume, including 71%, 72%, 73%,
74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, and 94%; about 2-15%
cyanoacrylate polymer, including about 3%, 4%, 5%, 6%, 7%, 8%, 9%,
10%, 11%, 12%, 13%, and 14%; and about 3-15% plasticizer, including
about 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, and 14%. Ranges
of percentages which comprise the preceding percentages and those
therebetween and are limited at their high and low ends by any two
of the recited percentages are also contemplated. For example, an
adhesive may comprise about 80-90% cyanoacrylate monomer, about
3-10% cyanoacrylate polymer, and about 5-10% plasticizer. In
another embodiment, an adhesive comprises about 84% cyanoacrylate
monomer, about 8% cyanoacrylate polymer, and about 8%
plasticizer.
[0045] In a preferred embodiment, the cyanoacrylate monomer
component comprises one or more cyanoacrylate monomer. By blending
monomers, the properties of the adhesive can be modified.
Cyanoacrylates with longer R groups can take a longer time to
polymerize; can have more flexibility; can have slower degradation;
and can have lower tensile strength. Also, cyanoacrylates with
longer R groups often utilize initiators to set or cure. On the
other hand, cyanoacrylates with shorter R groups can set very
quickly and release a significant amount of heat upon setting.
Hence, cyanoacrylates with shorter R groups may utilize stabilizers
to offset the quick setting and significant heat release. Also,
despite great tensile strength, cyanoacrylates with shorter R
groups tend to polymerize to produce a brittle material and are
prone to cracking and premature sloughing when used topically on
the skin. By combining a cyanoacrylate with a longer R group with a
cyanoacrylate with a shorter R group into blends, the properties of
the resulting adhesive can be modified. Although blends comprising
one or more cyanoacrylates having longer R groups and one or more
cyanoacrylates having shorter R groups are preferred in some
embodiments, blends may include only those having longer R groups
or only those having shorter R groups.
[0046] One preferred cyanoacrylate monomer component composition
comprises octylcyanoacrylate, as a cyanoacrylate with a longer R
group, and butylcyanoacrylate, as a cyanoacrylate with a shorter R
group. Such compositions preferably comprise about 50% to about 95%
octylcyanoacrylate and about 5% to about 50% butylcyanoacrylate,
including compositions having the following ratios of
octylcyanoacrylate to butylcyanoacrylate: 50:50, 55:45, 60:40,
65:45, 70:30, 75:25, 80:20, 85:15, 90:10, and 95:5. Ranges of
composition ratios which comprise the preceding ratios and those
therebetween and are limited at their high and low ends by any two
of the recited ratios are also contemplated. One of ordinary skill
of the art can optimize the properties of the cyanoacrylate monomer
component by routine experimentation with the amounts of the
members of the cyanoacrylate monomer component. In a preferred
embodiment, mixtures having higher levels of cyanoacrylates having
longer chain R groups further comprise an initiator to increase the
speed at which the adhesive sets up or cures. In the case of
octylcyanoacrylate, use of an initiator is preferred in those
embodiments having greater than about 80% octylcyanoacrylate.
[0047] In another embodiment, the cyanoacrylate monomer component
comprises a single cyanoacrylate monomer, with those having longer
chain R groups being preferred.
[0048] Depending upon the nature of the placement and composition
of the two surfaces to be joined, the degree of biodegradability or
bioabsorbability desired in the adhesive employed can vary. For
wounds or incisions on the surface of the skin, it can be
acceptable to use a adhesive that is only slowly degradable or
substantially nonbiodegradable. For example, it is preferable that
the adhesive material would slough off the surface of the skin in
about 7 to about 10 days. Alternatively, if both surfaces are
living tissues which are internal, it may be preferable to use an
adhesive that will biodegrade over a period of days or weeks,
diminishing as the natural healing mechanisms take hold.
[0049] If an adhesive having a chemical composition suitable for
use in wound closure does not have a viscosity in the preferred
range, the preferred working viscosity can be achieved in a variety
of ways. If the desired adhesive has a higher viscosity, such as
can be found with a thick gel or rubber-like material, the adhesive
can be combined with a solvent of high or moderate volatility to
lower the viscosity into the preferred range. The solvent could
then evaporate when it comes into contact with the warm surface of
the skin.
[0050] For thinner materials, which will likely form the great bulk
of desirable adhesives, the viscosity should preferably be
increased. If an adhesive sets up by means of polymerizing,
cross-linking or other curing mechanism, a partially cured adhesive
preparation can be used. By using a partially cured adhesive, the
viscosity could be brought within a suitable range for application
according to the discussion herein. Such an adhesive can be
prepared by initiating the curing mechanism and then quenching it,
such as by adding an inhibitor. The curing mechanism would then
need to be re-initiated prior to application, or immediately
thereafter. This type of method could be used for UV-curable
adhesives, for which re-initiation could begin by means of a UV
lamp or natural sunlight once the adhesive is removed or expressed
from its container. This method would also be suitable for
adhesives which set up in the presence of water, in that moisture
in the air or on the skin could provide the needed water, or the
site could be swabbed with water prior to application.
[0051] Although specific closure means and support structures are
identified and discussed in this specification, such use of the
terms should not be construed as limiting the definitions of these
terms. It is the applicant's intention that these terms be given
their broad ordinary meanings.
[0052] An adhesive according to preferred embodiments can be used
to effect wound or percutaneous incision closure in a manner that
is quick, simple, and effective. The preferred embodiments provide
for a method of closing a percutaneous opening, having a first
dermal surface on a first side of the opening and a second dermal
surface on a second side of the opening and generally coplanar with
the first dermal surface. The method comprises a step of applying
an adhesive layer across at least a portion of the first and second
dermal surfaces and spanning the opening. The materials and methods
of the preferred embodiments require little training for their use
and can be used by medical personnel to replace conventional
methods of closing wounds. Additionally, they can be used by
non-medical persons for use in combination with or as a replacement
for conventional home remedies, such as adhesive bandages.
[0053] In accordance with preferred embodiments, an adhesive is
used to join adjacent surfaces of skin to effect closure of a wound
or incision. The adhesive used in accordance with the preferred
embodiments are typically used as the primary closure modality, to
replace sutures or staples. The two sides to a percutaneous
incision, for example, can be held together and a layer of adhesive
can be placed on the surface to span the incision. After sufficient
polymerization, the adhesive will provide a strong bond while
natural healing processes occur under the surface. It is preferred
that the adhesives of the preferred embodiments are used as the
primary method of wound closure, but they can be used in
conjunction with other wound closure or tissue fastening systems,
such as staples and sutures, or in combination with a support
structure such as cloth or gauze.
[0054] Especially preferred adhesives are those which have a
viscosity such that, when it is placed on the skin, the adhesive
will span the gap between the two or more surfaces of the opening
with no flow into the opening or without flowing a substantial
distance into the opening. The opening spanned without substantial
seepage into the wound is generally about 0.1 mm to about 4 mm
wide, preferably 0.5 mm to about 1.5 mm wide, and for many
applications about 1 mm wide.
[0055] When adhesive is used having sufficient viscosity to span an
opening as described above, the adhesive can be made to form a
thicker layer above the wound than would be possible with a thinner
adhesive. This is because the more viscous adhesive will have a
greater resistance to flow under its own weight and will thus be
more likely to stay in a shape closely approximating that in which
it was applied. In one preferred embodiment, the adhesive, when
applied to the skin, has the profile seen in FIG. 6. Such a profile
can be achieved by using an applicator such as that shown in FIGS.
3 and 4 or by applying a generally rounded bead of adhesive to the
skin which then wets the skin surface. This profile of adhesive on
the skin, wherein the layer of adhesive 18 forming the closure is
relatively thicker in the area generally over the opening 20
between the pieces of skin 19, has advantages in that a thicker
layer of a given adhesive will have greater tensile strength than
will a thinner layer of the adhesive. The increase in tensile
strength of the material forming the closure will provide increased
protection against tearing or rupture of the opening following
sealing.
[0056] In addition to the foregoing, the adhesive materials may be
used as a secondary closure modality, being used in combination
with sutures, staples, and other such primary closures. In such
methods, the adhesive is applied to the surface of the wound or
incision, preferably after the wound is closed using the chosen
primary closure means. The use of an adhesive further strengthens
the closure and can also seal and protect the closure area.
[0057] The adhesive material according to the preferred embodiments
can also be used as a dressing to cover any trauma to the outer
layer of the skin. Trauma to the outer layer of skin includes, but
is not limited to, abrasions, scrapes, burns, blisters, bedsores,
ulcers, chapping, and chafing. The adhesive material is delivered
to a surface of the skin covering an area of the trauma to the
outer layer of the skin in a quantity sufficient to substantially
cover the trauma, or some portion thereof, and then is permitted to
polymerize or cure allowing healing underneath the polymerized
material.
[0058] In addition to using the adhesive material for closure and
sealing of wounds and as coverings for trauma to the outer layer of
the skin, the adhesive material may also be used as a surgical
adhesive to bind tissues within the body to other tissues or
materials. In such methods, a first surface and second surface are
joined using the adhesive material. A first surface to be joined
may be a surface of tissue in the patient, and the second surface
to be joined may be an autologous tissue from elsewhere in the same
patient such as a harvested vessel, allograph tissue such as a
human transplant organ from a separate donor, animal tissue such as
porcine or bovine heart valves, which may have been pretreated in
accordance with known technology, or any of a wide variety of
nontissue materials. Nontissue materials suitable for use with the
preferred embodiments include any of a variety of biologically
compatible metals such as stainless steel, gold, platinum, or
others well known in the medical device industry. The second
surface may also be any of a wide variety of polymeric materials,
including polyethylenes, polypropylenes, nylons,
polytetrafluoroethylene and other polyfluoro compounds, polyesters
such as Dacron, and other polymeric materials known in the art. The
second surface may also be a surface on any of a wide variety of
implantable prostheses, prosthetic devices, grafts or organs. For
example, the adhesive material may be useful in heart transplant,
kidney transplant, liver transplant, lung transplant or other
transplant procedures. In addition, a wide variety of vascular
grafting procedures can benefit from the use of adhesives according
to preferred embodiments, including tissue grafts using vessels
harvested from elsewhere in the patient's body, as well as
prosthetic grafts of the type which may be made from PTFE, Dacron,
or other materials, either alone or in combination with supporting
metallic cages. In addition, the adhesives may be used in
connection with the implantation of replacement heart valves which
will be subject to arterial pressure. Such valves may include
mechanical valves, bioprosthetic valves, and human allografts.
Although specific prostheses, prosthetic devices, grafts and organs
are named and discussed herein, such use of the terms should not be
construed as limiting the definitions of these terms. It is the
applicant's intention that these terms be given their broad
ordinary meanings. Additionally, the terms device, graft,
prosthesis and organ should be interpreted as including any skirts,
supports, coverings or additional materials attached to or
associated with the device, graft, prosthesis or organ.
[0059] In addition to the foregoing, the adhesive material may also
be used for skin, cartilage and bone grafting, sealing
cerebrospinal fluid leaks, Tympanoplasty, ossiculoplasty, sealing
bowel and vascular anastomosis, sealant for fractured teeth, and
dressing for Aphthous ulcers.
[0060] The surgical method proceeds by bringing together the two
surfaces that will form the joint and initially securing them
together by a primary closure, including, but not limited to, those
formed by the use of sutures, staples, or other materials and
methods known in the art. The joint between the two surfaces is
then sealed and further secured by applying the adhesive to the
interface of the two surfaces. The method of application may, in
part, be determined by factors such as the characteristics of the
chosen adhesive and the geometry, size and placement of the
application site. If required, the two surfaces are held together
by use of a suitable surgical instrument for the time required for
polymerization of the adhesive.
[0061] Alternatively, the two (or more) surfaces may be brought
together by clamps, forceps, hands or other removable means and
secured and sealed by means of the adhesive alone, with the
adhesive being applied in a quantity sufficient to retain closure
or attachment of the surfaces. The adhesive may be applied to one
or both surfaces, either before or after the surfaces are brought
together. After polymerization to the point of adhesion, the
clamps, forceps or the like are then removed such that the adhesive
is the primary or even the only securing modality.
[0062] In other methods, the adhesive material is applied directly
to a small opening, such as a puncture, in a quantity sufficient to
close and seal the opening. In the case of a very small opening,
the adhesive material can close the opening without any need for a
separate step of bringing together two or more surfaces to be
secured together.
[0063] Preferably, the adhesive material is allowed to dry,
polymerize and/or cure following its application. The
polymerization rate of the adhesive material should be such that
the time to set the adhesive material should not be too short or
too long and suitable for the clinical indication. A short
polymerization time would allow little if any margin for error for
sealing surfaces. A long polymerization time would not allow the
convenience of a quick-sealing adhesive. Hence, a preferred set-up
time for the adhesive material is about 10 to about 180 seconds,
more preferably about 15 to about 90 seconds, including 20, 30, 40,
50 and 60 seconds. The curing time is the time for the adhesive
material to obtain maximal strength and completely dry and
polymerize. In one embodiment, preferred curing times for the
adhesive material are about 1 to about 5 minutes, including about
2, 3 and 4 minutes.
[0064] What follows is a discussion of several applicators and
methods of applying the adhesives of the preferred embodiments. It
is contemplated that any of the adhesives described herein can be
used in connection with the devices and methods described as well
as with other devices and methods as will be apparent to those
skilled in the art.
[0065] Any of a variety of containers, made of materials such as
glass, plastic or aluminum, or devices can be used to apply or
deliver adhesive to a wound for closure and sealing. For example,
syringes, eyedroppers, compressible bottles or tubes, tongue
depressors, spatulas, and the like can be used to deliver adhesive
to the site intended for sealing. Adhesive can also be applied
manually without the use of an applicator. Additionally, devices
designed to deliver sealing adhesive can be used, such as that
disclosed in U.S. Pat. No. 5,529,577. Once they are formulated,
adhesives may be placed in container-applicators such as those
discussed in greater detail below. The choice of application or
delivery means can, in part, be determined by the viscosity of the
adhesive employed. The choice of delivery means can also depend on
other factors, such as the nature, physical structure, and location
on the body of the wound, incision or other opening to be closed
and sealed.
[0066] Proper storage of tissue adhesives is an important
consideration. For example, if a UV-curing adhesive is used, the
storage container preferably prevents penetration of UV radiation,
and if a water-curing adhesive is used, a desiccant may be used.
Because many cyanoacrylates will polymerize and harden relatively
rapidly when stored below a critical volume, it is preferable for
the vessel or reservoir in which the adhesive is stored to contain
more adhesive than is necessary to seal a typical site. Preferably,
the storage vessel or reservoir in a single-use container or
container-applicator will contain a minimum of about 0.2 to about 5
grams of adhesive or more to maintain the cyanoacrylate monomer
component in a generally unpolymerized state in the storage vessel
or reservoir prior to use. For multiple-use containers or
container-applicators, the reservoir preferably contains about 1 to
about 10 grams, more preferably about 3 to about 5 grams of
adhesive. In certain embodiments, the volume of the container is
half filled to help maximize shelf life. The total volume of
adhesive, the desiccation measures, and the sealing structures in
the container or container-applicator can be optimized by one of
skill in the art to provide enhanced shelf life.
[0067] The tissue adhesives of the preferred embodiments are
preferably stored and applied using a container-applicator. A
container-applicator has two basic parts: (1) a storage area or
reservoir which holds the adhesive and protects it from air, water
and contaminants; and (2) the applicator which comprises a
specially shaped tip designed to aid in application of
adhesive.
[0068] The reservoir is preferably both air-tight and water-tight,
and keeps the adhesive within free from contaminants. The reservoir
can contain a desiccant material to keep the adhesive free of
water, which would cause polymerization of the preferred
cyanoacrylate-based adhesive. Reservoirs can be of any shape,
although shapes which provide for a smooth internal flow of
adhesive, such as cylindrical or pyramidal shapes, are preferred.
The size of the reservoir can vary within a wide range, but is
preferably slightly larger than the volume of adhesive which will
be placed inside the reservoir to minimize the amount of gas within
the reservoir. The reservoir can be made from any of a variety of
medical grade materials, such as plastics, that is suitable for the
storage of cyanoacrylates as is known in the art. The reservoir can
be either rigid, collapsible, or compressible. Use of a
compressible or collapsible reservoir allows the user to have
greater control over the rate at which adhesive is expressed, as
exertion of pressure on a compressible or collapsible reservoir
would place a force on the on the adhesive causing it to flow at a
faster rate than it would in the absence of such pressure. The
compressible or collapsible reservoir design is especially
preferred for highly viscous or gel-like adhesive for which the
force of gravity may not be strong enough to cause a flow of
adhesive through an applicator sufficient to close a wound.
Collapsible reservoirs which retain their collapsed shape have the
additional advantage of reducing the amount of air which enters the
reservoir following use. This advantage of collapsible containers
is of greater importance in multiple-use (reusable) devices,
wherein adhesive is preferably kept relatively free of potential
contaminants between uses.
[0069] Applicator tips can be of any of a number of shapes, sizes,
and configurations. They are preferably fairly rigid and may be
made out of any material which is compatible with the adhesive
formulation, and may be plastic, cotton tipped swabs or high
density foams, preferably plastic. The choice of a proper
applicator tip for a given application will depend on factors such
as the viscosity of the adhesive, the desired application rate of
the adhesive, the nature of the wound, the placement of the wound
on the body, and the physical structure of the wound.
[0070] The container-applicators of the preferred embodiments can
be either single-use or multiple-use devices. For most
applications, single-use container-applicator devices are
preferred. This preference arises because the risk of
cross-contamination between wounds or patients is practically
eliminated when a new device is used for each closure. As an
alternative to the single-use embodiment, a container or reservoir
containing enough adhesive for multiple closures may be configured
to accommodate replaceable tips. In such an embodiment, at the
place whereon the replaceable tips connect with the reservoir, the
reservoir would preferably have a means such as a valve, septum or
sealing gasket which allows the reservoir to be sealed in the
absence of an applicator tip. Placing an applicator tip on the
reservoir would cause the valve to open, allowing adhesive to flow
out from the reservoir. In this manner, one reservoir containing
enough adhesive to close several wounds could be used over a period
of hours, days or weeks. This embodiment would also allow the user
to use one reservoir with applicator tips of varying shapes and
sizes chosen to best accommodate the needs of different wounds.
[0071] Three specific embodiments of container-applicators are
depicted in the drawings and detailed below.
[0072] One preferred embodiment of container-applicator is the
rollerball container-applicator 1 depicted in FIG. 1. The reservoir
2 can be either rigid, compressible, or collapsible and can be made
out of any material suitable for the storage of cyanoacrylates, as
is known in the art. The applicator tip portion of the
container-applicator comprises a ball 3 and a cuff 4. The ball 3 is
held loosely within the cuff 4 so that the ball 3 is free to rotate
in any direction, but not so loosely as to allow the ball 3 to be
removed or fall out when the container-applicator 1 is inverted.
The size of the gap 5 formed between the ball 3 and the cuff 4 can
be varied to accommodate a wide range of viscosities of adhesive
and desired flow rates. For low viscosity adhesives, a relatively
small gap 5 would be preferred to allow the adhesive to flow out
around the ball at a reasonable rate during application, whereas
for high viscosity gel-like adhesive a larger gap 5 would be
required to allow a reasonable flow of adhesive around the ball 3.
Similarly, the gap 5 can be varied to achieve a desired application
rate for adhesives of a particular viscosity. For adhesive of a
given viscosity, a large gap 5 would provide a higher flow rate for
the adhesive than a smaller gap 5. Furthermore, use of a
compressible or collapsible reservoir 2 allows for additional
control over the rate at which adhesive is expressed, as exertion
of pressure on the compressible reservoir increases the pressure on
the adhesive causing it to flow through gap 5 at a rate faster than
that for the same adhesive in the absence of exerted pressure,
regardless of viscosity.
[0073] A second embodiment of container-applicator is that depicted
in FIG. 3. This embodiment comprises a reservoir 11 and an
applicator tip 12. The container-applicator 10 can further comprise
a one-time removable or breakable sealing tip or cap as described
below. In the illustrated embodiment, the adhesive flows from the
reservoir 11 through a tubular extension 12 and out to the
application site through an opening 13 in the distal end of the
applicator tip 14. In one preferred embodiment, the length of the
extended portion 12 of the applicator tip 14 is preferably about
0.1 to about 10 cm long, more preferably about 0.5 to about 2 cm,
but can be readily optimized in view of an intended use for the
applicator 10. The distal end may be flared, as shown, and its
largest cross-section can also come in a wide range of sizes,
preferably from about 0.5 to about 5 cm, generally less than about
2 cm, but it is most preferably chosen to be larger than the width
of the wound to be closed. The configuration of the opening 13 can
be a narrow elliptical or rectangular slot or other configuration
suited for the end use. The reservoir 11 is preferably compressible
or collapsible to allow for greater control in the rate at which
the adhesive is expressed from the opening 13. The reservoir may
comprise any suitable material, including metal (such as metal
foil) and plastic and combinations thereof.
[0074] In one embodiment, the distal opening 13 of the applicator
tip 14 has a shape like that shown in FIG. 4. During application,
the flattened side is placed towards the skin to maximize the area
of applicator-skin contact. This semi-elliptical or other concave
shape of the opposing side of opening 13 results in application of
a rounded strip of adhesive as the tip 14 is drawn across the
surface of the skin. Center thickness on the order of at least
about 2 times and often as much as about 3 or about 5 times or
greater the edge thickness are preferably achieved. This shape
optimizes adhesive tensile strength across the top of the wound. In
general the combination of thickness and inherent adhesive
characteristics for a particular adhesive should be optimized to
provide both a sufficient bond to the skin as well as sufficient
tensile strength to resist tearing under reasonably anticipated
forces encountered by normal activities of the patient. Although
this tip shape has advantages in accordance with some embodiments,
use of tips having other shapes and configurations are
contemplated, including a dropper tip, tube, opening between two
sheets of foil, and the like.
[0075] The applicator tip of the container-applicator can further
comprise a removable or breakable sealing tip. One embodiment of a
breakable sealing tip, which can be used for a single-use device,
is shown in FIG. 5. The applicator cap 15 forms a solid covering
for the opening of the applicator tip (14 in FIG. 5). The
applicator cap 15 is preferably of the same material as the
applicator tip 14, the two parts meeting at a breakline 16. In one
embodiment in which the tip 14 and cap 15 are integrally formed,
the breakline 16 is characterized by scoring or other means which
weakens the junction and allows the two parts to be easily
separated by grasping the two parts (12 and 15) in either hand and
bending or tearing the pieces apart to expose the opening 13 in the
applicator tip 12 through which the adhesive is expressed. The cap
15 can alternatively be press fit or threadably engaged within or
over the distal tip 14 and retained by friction as will be apparent
to those of skill in the art.
[0076] Alternatively, a single-use device can comprise a reservoir
wherein the opening through which the adhesive flows is covered
with a peelable or puncturable plastic film or metal foil. In one
such embodiment, the foil or film is peeled back or pierced prior
to positioning the applicator and sealing the wound. In another
embodiment, the applicator portion has a proximally extending point
or projection which pierces the foil or film as it is threaded onto
or otherwise secured to the reservoir. As shown in FIG. 7, a
certain embodiment comprises inert collapsible or compressible
metal foil tubes with long-necked applicators. Adhesive material is
easily delivered from the tube 22 by puncturing a seal 24 of a
screw 26 on top of the container-applicator. A long-necked screw 28
with a cannula 30 is positioned tightly with the screw 26 of the
container-applicator. The adhesive material can be expressed
through an orifice of the cannula and applied evenly with a beveled
length of the cannula to a desired thickness of adhesive material.
The long neck applicator can be catheter like device with orifices
of 20-25 gauge and 1 in in length.
[0077] One embodiment of container-applicator is a single-use,
sterile wound closure device. Preferably such a device has a
pierceable or removable tip seal. The container portion of the
preferred single-use wound closure device is sized to hold
preferably from about 0.2 to about 1.0 grams, more preferably about
2 g of tissue adhesive, depending upon the intended use. The
container can be of any of a variety of standard container shapes,
and is preferably compressible or collapsible so that the user may
control the rate at which the adhesive contained therein is
expressed by varying the pressure exerted on the walls of the
container.
[0078] The single-use sterile wound closure device is prepared by
first taking a clean container that will serve as the reservoir and
filling it with adhesive. The reservoir is then sealed. Sealing the
reservoir is preferably done by affixing an applicator tip with a
removable seal to the reservoir, or by securing a pierceable septum
to the container. The container-applicator, with the adhesive
sealed inside, is then sterilized by methods known to those skilled
in the art which can be used on the materials from which the
container-applicator is made and which will also not react with the
adhesive.
[0079] In the alternative, the pieces which comprise the
container-applicator can be pre-sterilized, and the device filled
and sealed in a sterile or ultra clean environment. This is
potentially a viable method, as a preferred adhesives comprising
cyanoacrylates are generally not supportive of the growth of
microorganisms.
[0080] The use of reusable coverings for applicators or applicator
openings, such as caps, plugs, valves, or the like are also
contemplated. Use of this type of covering would allow a container
or container-applicator to be used several times before it is
discarded.
[0081] The containers, applicators, and container-applicators
disclosed above can be used alone, in combination with a support
structure, such as a piece of cloth, gauze or mesh, or in addition
to some other securing means such as sutures or staples. Support
structures can provide an extra measure of strength and protection
for the wound, while use of a adhesive with sutures or staples can
reinforce and thoroughly seal the joint to help prevent rupture,
protect the joint from abrasion, or keep it free of debris.
Similarly, for a deep or penetrating wound or surgical incision,
the innermost tissues can be joined by dissolvable sutures while
the exterior surface is joined using adhesives according to the
preferred embodiments.
[0082] Closure of a wound can also be effected by the use of a
device comprising a support structure impregnated with adhesive. In
such a device, the support structure, comprising cloth or gauze,
has a sufficient quantity of adhesive imbedded therein to allow for
closure and sealing of a wound. Preferably, each device is
individually sealed within air-and-water-tight packaging such as a
plastic or foil pouch until use. Although the application and use
of such a device would be very similar to a conventional adhesive
bandage, it has several advantages. The adhesive impregnated
support structure will adhere to the wound for a much longer time
than a conventional adhesive bandage and provide a better barrier
to water, dirt, and abrasion. The adhesive impregnated support
structure would be especially suitable for use on children, as it
would keep the wound cleaner and prevent the child from disturbing
the wound and hampering the healing process.
[0083] Alternatively, an adhesive material according to preferred
embodiments may be applied over an adhesive tape. The adhesive
material is preferably applied over the adhesive tape in a quantity
sufficient to penetrate the tape and provide additional securement
force to maintain closure of the wound. The adhesive material
covering can also aid in reducing lifting or separating of the tape
from the skin and serve as a barrier to moisture or
contamination.
[0084] Generally the methods of the preferred embodiments proceed
by delivering the appropriate adhesive to the percutaneous opening.
Following application, the adhesive is allowed to set up. Methods
of the preferred embodiments can optionally include steps of
bringing the sides of the wound into opposition, applying another
closure modality to be used in conjunction with the adhesive,
and/or holding the surfaces together until the adhesive has
adequate strength to hold the opening closed.
[0085] In a preferred embodiment, the adhesive takes on a
bell-curve type shape as shown in FIG. 6 following application.
This shape is advantageous in that it places the thickest part of
the layer, and thus the strongest part of the layer, over the
opening in the skin to provide enhanced resistance to tearing,
rupture, or other stress or damage to the opening following
closure. The added protection provided by a thicker layer can aid
in speeding the healing process and allowing for a minimum of
stretching of the wound as it heals, which may help minimize
scarring. The adhesive can be applied such that the thickness over
the percutaneous opening is at least about 0.1 mm, often from about
0.5 mm to about 4 mm thick, or from about 1.0 to about 2.5 mm
thick.
[0086] In one embodiment, an adhesive is used for which the
polymerization process of the adhesive is enhanced by the presence
of water or a basic substance. Prior to application of the
adhesive, water is optionally placed on the skin in the general
area of the wound or opening, including a spraying or misting water
or saline on the area, or wiping the area with an alcohol/water
prep pad. The water which remains on the surface may increase the
rate at which the adhesive sets up on the wound. However, it should
be noted that in some cases the presence of additional water may
impair crosslinking and the polymerization and eventual tensile
strength of the adhesive.
[0087] Initiators, cross-linkers, catalysts, and other compounds
which aid an adhesive in setting up can be applied in a similar
manner, provided that they would not irritate the open wound, or
cause other undesirable side effects.
[0088] When applying adhesive of the preferred embodiments, the
surfaces of the wound, laceration, percutaneous incision, or the
like intended for closure are brought in contact with each other by
use of the fingers, forceps, or a similar device. A sufficient
amount of adhesive is delivered to the surface so that proper
sealing and closure retention will occur. When sealing the joint
formed by the sides of the wound, laceration, or percutaneous
incision, the adhesive is applied to the exterior surface of the
wound and allowed to polymerize so that it forms a film over the
entire wound. Preferably, adhesives are applied in a manner to
minimize the amount of adhesive which seeps between the edges of a
wound. The amount of adhesive to apply in any given case, and thus
the area and thickness of the resulting film, can depend on several
factors including placement of the wound on the body, depth of the
wound, tissue sensitivity to the adhesive, and the like. Adhesive
can be applied alone or in combination with a support structure or
other securing means such as sutures. Through routine
experimentation, however, one of skill in the art will be able to
exercise clinical judgment to determine an appropriate quantity of
adhesive to provide effective closure for a particular
procedure.
[0089] Methods of the preferred embodiments are preferably directed
toward closing and sealing a wound by sealing and securing together
adjacent tissues, such as opposing pieces of skin, in a patient.
The need for closure of such a wound can arise during surgical
procedures, as a result of percutaneous incision. The need can also
arise as a result of traumatic injury resulting in a laceration or
other wound which breaks the skin.
[0090] Generally, a method of closing a wound, laceration,
percutaneous incision, or the like proceeds by first assessing what
type of closure or combination of closures is proper for a wound
given factors such as the size, depth, and location of the wound as
well as an assessment of the overall needs and requirements of the
patient. Such assessments are routinely done by those skilled in
the medical arts. In a non-clinical setting, the assessment step
will likely be much more cursory.
[0091] Next, a suitable formulation of adhesive, an applicator, and
a method of application are chosen. These three choices are
somewhat interconnected, as the choice of a particular applicator
constrains the method of application, and a particular formulation
of adhesive can constrain the type of applicator or method of
application which can be used, and vice-versa.
[0092] The choice of a suitable formulation of wound closure
adhesive, as disclosed herein, can depend upon characteristics of a
adhesive such as its viscosity, biodegradability and rate thereof,
resulting tensile strength upon polymerization, flexibility when
polymerized, histotoxicity, and polymerization rate. Specific
characteristics can be desired to fit clinical needs as dictated by
factors such as the size of the wound, the amount and rate of
bleeding from the wound, the location of the wound on the body, and
potential stress on the sealed wound.
[0093] The choice of applicator and method of application can, in
part, be determined by factors such as the composition, viscosity,
and polymerization time of the adhesive, and the geometry, size and
placement of the application site. Such a choice can also be
constrained by the tools and devices available to the user.
Examples of preferred applicators are disclosed above and examples
of preferred methods of application are described below.
[0094] Next, the wound may need to be prepared before closure.
Activities involved in wound preparation are highly situational,
but are routinely done by those skilled in medicine, nursing, and
related arts. Wound preparation can involve tasks, such as removal
of debris, dirt, oil, or excess tissue from the wound, application
of pressure or similar measures to bring about the cessation of
bleeding, cleansing the wound, application of an antimicrobial
preparation, use of additional closure means such as sutures, and
other such tasks. In a non-clinical setting, the patient or use can
also perform some of these same tasks.
[0095] If the surfaces of the wound naturally pull apart, it can be
advantageous to bring the two surfaces into contact with each other
and align them by use of the fingers, support structure, forceps or
other suitable medical instrument. In such a case, the two surfaces
are preferably held together as the adhesive is applied and
afterwards until sufficient polymerization has taken place to allow
the closure to be self-supporting. Alternatively, the two surfaces
can be brought together by sutures, staples, tape or other securing
means and then further sealed by application of a chosen adhesive.
Such methods can allow for eventual scarring of the opening to be
minimized. In wounds for which the skin is not separated, this step
can be skipped.
[0096] The chosen adhesive is then applied using the applicator and
method chosen in an earlier step. The entirety of adhesive
application is preferably done within a limited period of time, as
the strength of the closure formed by two or more successive
applications of adhesive (wherein one application has been allowed
to polymerize before the next application) may not be as strong as
the closure formed by one application allowed to polymerize to form
a single layer on the skin surface. Adhesive is applied in a
quantity sufficient to effect wound closure and sealing. More can
be applied, if desired, to increase the strength of the closure as
discussed above, or likewise a support structure may be applied.
Determination of quantity of adhesive applied can be determined by
routine experimentation and exercise of clinical judgment. Specific
methods of application involving the use of container-applicators
are discussed in the paragraphs which follow.
[0097] One specific method of application is that involving the use
of the rollerball container-applicator pictured in FIG. 1. To use
this container-applicator, first any sealing means is removed or
broken. Then, as depicted in FIG. 2, the container is tipped so
that the rollerball is pointing in a generally downward direction
and the bottom of the reservoir portion is pointing in a generally
upward direction. Such orientation of the container-applicator
facilitates the flow of adhesive towards the rollerball applicator
portion through which it can then be applied to the wound.
Preferably the adhesive is applied by moving the
container-applicator back and forth over the surface of the wound
and surrounding skin areas while keeping the rollerball in contact
with the wound at all times. Although a back and forth movement is
preferred, any movement of the applicator which serves to deliver
the adhesive to the intended site without disturbing the wound
itself is contemplated.
[0098] If the reservoir portion of the container-applicator is
compressible or collapsible, the rolling of the applicator over the
surface of the skin can be accompanied by squeezing or otherwise
compressing the walls of the reservoir. With such a collapsible or
compressible reservoir, the rate of flow of adhesive and therefore
the amount of adhesive delivered, is proportional to the amount of
pressure applied to the walls of the reservoir. The quantity and
rate of adhesive delivery can thus be controlled by the user.
[0099] Another specific method of application is that using a
container-applicator of the type depicted in FIG. 3. To apply
adhesive, first any sealing means such as a foil seal, peel-away
thin film or breakable tip is punctured or removed to allow for
flow of adhesive. The applicator tip is preferably placed on or
slightly above the surface of the wound to be sealed. If a
semi-elliptical tip is used, such as that pictured in FIG. 4, the
flattened side is preferably placed closest to the skin. The
adhesive is then allowed to flow through the applicator and onto
the surface of the skin forming a profile such as shown in FIG. 6.
Preferably, the reservoir portion comprises collapsible or
compressible walls such that the user may exert pressure on the
walls to facilitate the delivery of adhesive to the skin, and thus
control the rate at which the adhesive is expressed from the
applicator tip. The tip is moved over the surface of the skin,
following the contours of the wound, resulting in the deposition of
a strip of adhesive on the skin covering the wound. Additional
strips may be laid down in a similar manner to thicken or expand
the area of adhesive coverage.
[0100] In accordance with another embodiment, the reservoir is
provided as a separate component from the applicator tip. In this
embodiment, the reservoir is provided with a pierceable seal or
septum, such that a unit volume of adhesive can be sealed within
the reservoir. Pierceable septums or seals comprising silicone,
other polymeric materials known in the medical industry, as well as
metal foils or thin polymeric films may be utilized, as will be
apparent to those of skill in the art in view of the nature of the
complimentary piercing structure on the applicator tip.
[0101] The detachable applicator tip comprises an applicator
surface on a distal side thereof, and a cannula, needle or other
piercing structure projecting proximally from a proximal side
thereof. A retention structure is preferably also provided, for
securing the applicator tip to the reservoir. In one embodiment,
the retention structure is an axially extending annular flange
having a thread on the radially inwardly or outwardly facing
surface thereof, for threadably engaging the top of the reservoir.
Any of a variety of other retention structures can be utilized, as
will be apparent in view of the disclosure herein.
[0102] Prior to use at the clinical site, the applicator tip is
secured to the reservoir such that the proximally extending
piercing member on the proximal side of the applicator tip pierces
the septum or other seal on the reservoir, thereby placing the
contents of the reservoir in fluid communication with the distal
applicator surface. This embodiment is particularly suited for a
one-time use disposable device. The applicator surface can be of
any of a variety of structures disclosed elsewhere herein, such as
a rollerball, or a specially configured opening such as a slot, for
expressing a thin layer of sealing adhesive over the surface of the
tissue on either side of a wound.
[0103] Any of the foregoing methods can be combined with the
application of a support structure, such as gauze. A layer of
adhesive is first applied to the wound, onto which gauze or other
support structure is affixed, the adhesive acting to secure the
gauze in place. More adhesive may then be applied over the gauze to
further secure it and strengthen the closure. In the alternative,
gauze can be first placed over the wound and then covered and
secured to the wound by subsequent application(s) of adhesive as
described above. In either case, alternate layers of adhesive and
gauze may be applied to form a flexible, reinforced structure which
effects closure of the wound and sealing.
[0104] As an alternative to the method discussed above, a
prepackaged adhesive-impregnated support structure can be applied
to the wound to achieve closure. Such a device, as described above,
is preferably packaged in a sealed pouch and comprises a support
structure, such as a section of cloth, that is saturated with a
quantity of adhesive sufficient to allow for attachment of the
support structure and effect closure of a wound or section of a
wound of a size corresponding to the size of the support structure.
Closure of a wound using such a device is somewhat comparable to
using a common adhesive bandage and is particularly well-suited for
non-clinical use. First, the pouch containing the device is opened
and the device removed therefrom. The device is then placed over
the surface of the wound and then pressed into place to ensure good
contact between the device and the skin. If additional coverage is
required or desired, additional devices may be applied. When more
than one device is used, they are preferably applied within a short
time of each other so that they polymerize at nearly the same
time.
[0105] The various methods and techniques described above provide a
number of ways to carry out the invention. Of course, it is to be
understood that not necessarily all objectives or advantages
described may be achieved in accordance with any particular
embodiment described herein. Thus, for example, those skilled in
the art will recognize that the methods may be performed in a
manner that achieves or optimizes one advantage or group of
advantages as taught herein without necessarily achieving other
objectives or advantages as may be taught or suggested herein.
[0106] Furthermore, the skilled artisan will recognize the
interchangeability of various features from different embodiments.
Similarly, the various features and steps discussed above, as well
as other known equivalents for each such feature or step, can be
mixed and matched by one of ordinary skill in this art to perform
methods in accordance with principles described herein.
[0107] Although the invention has been disclosed in the context of
certain embodiments and examples, it will be understood by those
skilled in the art that the invention extends beyond the
specifically disclosed embodiments to other alternative embodiments
and/or uses and obvious modifications and equivalents thereof.
Accordingly, the invention is not intended to be limited by the
specific disclosures of preferred embodiments herein, but instead
by reference to claims attached hereto.
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